5-Fluorouracil (5 FU) is a fluorinated pyrimidine exhibiting antimetabolite activity and is a known antineoplastic agent.
5FU has long been used as a drug for the palliative management of various carcinomas including carcinoma of the colon, rectum, breast, stomach, and pancreas. It is frequently used in patients who are considered incurable by surgery or other means.
This compound is thought to interfere with the synthesis of DNA and to a lesser extent inhibits the formation of RNA. Since DNA and RNA are essential for cell growth and division, the effect of 5FU may be to create a thymine deficiency which provokes unbalanced growth and death of the cell. The effects of DNA and RNA deprivation are most marked on cells such as carcinoma cells which grow most rapidly.
5FU is an article of commerce and is generally supplied for intravenous injection in 10 ml. ampuls at a concentration of 50 mg/ml. The current 5FU formulations are colorless to faint yellow aqueous solutions which are at a pH of about 8.8. The current fluorouracil formulations are also temperature sensitive and must be stored at a temperature of above about 60.degree. F. in order to avoid precipitation. Often, during shipment of the drug from, supplier to user they are exposed to temperatures below this range. The ampuls may arrive at their destination with the 5FU precipitated into large agglomerates which render the product unsuitable for use in that form.
The precipitate formation at low temperatures during winter shipment is a statistical phenomenon and occurs frequently. The precipitation yields large initial heterogenous nucleation at a few sites, and subsequent secondary growth. This necessitates the inconvenience of resolubilizing by heating to 140.degree. F. with vigorous shaking. The solution must then slowly be cooled to body temperature before administration.
Heretofore, it has not been possible to distribute a 5FU formulation in a sealed container suitable for administering an injectable unit dose where the contents do not precipitate upon exposure to the low temperatures which often occur during shipment. With vial formulations precipitation at lower temperatures is particularly problematic, and may occur at temperatures and conditions where the corresponding ampul formulations would remain stable.
Accordingly, there has long been a need for a stable 5FU formulation suitable for storage in a sealed container suitable for administering an injectable unit dose where the contents do not precipitate at the temperatures below about 60.degree. F. which often occur during shipment.